Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS
Journal
npj Genomic Medicine
ISSN
2056-7944
Date Issued
2023
Author(s)
Yingjie Zhao
Yujue Wang
Lijie Shi
Donna M. McDonald-McGinn
T. Blaine Crowley
Daniel E. McGinn
Oanh T. Tran
Daniella Miller
Jhih-Rong Lin
Elaine Zackai
H. Richard Johnston
Eva W. C. Chow
Jacob A. S. Vorstman
Claudia Vingerhoets
Therese van Amelsvoort
Doron Gothelf
Ann Swillen
Jeroen Breckpot
Joris R. Vermeesch
Stephan Eliez
Maude Schneider
Marianne B. M. van den Bree
Michael J. Owen
Wendy R. Kates
Vandana Shashi
Kelly Schoch
Carrie E. Bearden
M. Cristina Digilio
Marta Unolt
Carolina Putotto
Bruno Marino
Maria Pontillo
Marco Armando
Stefano Vicari
Kathleen Angkustsiri
Linda Campbell
Tiffany Busa
Damian Heine-Suñer
Kieran C. Murphy
Declan Murphy
Sixto García-Miñaúr
Luis Fernández
Tiffany Busa
Zhengdong D. Zhang
Elizabeth Goldmuntz
Raquel E. Gur
Beverly S. Emanuel
Deyou Zheng
Christian R. Marshall
Anne S. Bassett
Tao Wang
Bernice E. Morrow
Type
Resource Types::text::journal::journal article
DOI
URL
Abstract
<jats:title>Abstract</jats:title><jats:p>Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40–50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of <jats:italic>TBX1</jats:italic>, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the <jats:italic>TBX1</jats:italic> gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include <jats:italic>EP400</jats:italic>, <jats:italic>KAT6A</jats:italic>, <jats:italic>KMT2C</jats:italic>, <jats:italic>KMT2D</jats:italic>, <jats:italic>NSD1, CHD7</jats:italic> and <jats:italic>PHF21A</jats:italic>. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with <jats:italic>TBX1</jats:italic>, suggesting that they may be in the same genetic network. The genes <jats:italic>KAT6A</jats:italic>, <jats:italic>KMT2C</jats:italic>, <jats:italic>CHD7</jats:italic> and <jats:italic>EZH2</jats:italic>, have been previously shown to genetically interact with <jats:italic>TBX1</jats:italic> in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the <jats:italic>TBX1</jats:italic> gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the <jats:italic>TBX1</jats:italic> gene network in the etiology of CHD.</jats:p>